Inflammasome activation by cholesterol crystals

胆固醇晶体激活炎症小体

基本信息

批准号：
8459032
负责人：
Eicke Latz
金额：
$ 38.76万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459032
关键词：
Appearance Arterial Fatty Streak Arteries Atherogenic Diet Atherosclerosis Biological Testing Blood Blood Vessels Breeding Cardiovascular Diseases Caspase-1 Cathepsins Cell Wall Cells Cholesterol Chronic Disease Cleaved cell Clinical Complex Connective Tissue Crystal Formation Crystallization Cytoplasmic Protein Data Development Disease Elements Epidemiology Extracellular Space Foam Cells Growth Factor Human Image Imaging Techniques Immune Immune response Immunofluorescence Immunologic In Vitro Infection Inflammation Inflammatory Interleukin-1 Interleukin-18 Knockout Mice Knowledge Lead Lesion Link Lipids Liquid substance Low Density Lipoprotein Receptor Low-Density Lipoproteins Malignant Neoplasms Mediating Metabolic Microbe Microscopy Modeling Molecular Molecular Target Morbidity - disease rate Mus Pathologic Pathology Pathway interactions Play Prevalence Process Reaction Resolution Risk Role Signal Transduction Societies Staging Structure Testing Tissues base cytokine cytosolic receptor economic impact feeding immune activation improved in vivo inhibitor/antagonist insight macrophage mortality new therapeutic target novel particle pathogen prevent protein complex receptor socioeconomics

项目摘要

Atherosclerosis is a chronic disease of arterial blood vessels and is fundamentally linked to abnormally high blood cholesterol levels. Atherosclerotic lesions develop after excessive amounts of lipids accumulate in arterial walls. Macrophages in atherosclerotic lesions take up and store large amounts of lipids during which they are activated to produce inflammatory cytokines and growth factors. The local saturation of free cholesterol can lead to crystal formation inside macrophages and in the extracellular space. Inflammatory immune responses in atherosclerotic lesions are key pathogenic factors for the development of clinical disease. However, the factors leading to the activation of inflammation in atherosclerotic lesions remain unknown. Immune cells recognize and respond to conditions that are of danger to the host, such as infections, cancer, tissue damage or metabolic derangements. Immune cells express receptors that can recognize foreign molecules from microbes as well as altered self-molecules, which appear under pathologic conditions. It has recently been shown that crystallization of normally soluble material is perceived as a danger to the host and can lead to the activation of the cytosolic receptor complex NALP3 inflammasome. We found that cholesterol crystals, which are abundantly present in atherosclerotic lesions, could activate the NALP3 inflammasome in immune cells leading to caspase-1 mediated maturation and release of the pro-inflammatory cytokines IL-1¿ and IL-18. Our hypothesis is that cholesterol crystals act as an endogenous danger signal and activate the NALP3 inflammasome. We postulate that cholesterol crystal-induced immune activation is fundamental for the development of inflammation in atherosclerotic lesions and could influence the initiation and progression of atherosclerotic disease. We propose to study the molecular mechanisms of cholesterol crystal recognition by analyzing mice with targeted lesions in components of the inflammasome pathway. Macrophages from knock-out mice will be analyzed in vitro and cholesterol crystal-induced inflammation will be tested in vivo. To better understand how crystals can enter macrophages and where signaling is initiated, we will make use of confocal imaging techniques that image crystals together with fluorescent structures at high spatial resolution. We will test the biological relevance of NALP3 inflammasome activation using a mouse atherosclerosis model with double knock-out mice that lack the LDL receptor and components of the inflammasome (NALP3 and ASC) pathway. We will further assess the prevalence of crystals in different human artherosclerotic lesion types together with cellular and inflamasome activation markers to gain insights into the relevance of crystals in human atherosclerotic disease. Detailed knowledge of the molecular mechanisms of cholesterol crystal recognition by immune cells will aid in the identification of novel therapeutic targets directed against the onset and progression of atherosclerosis, which could have broad clinical and socio-economic impact.

动脉粥样硬化是一种动脉血管的慢性疾病，从根本上与绝对高有关血液胆固醇水平。在累积过多的脂质后，动脉粥样硬化病变会出现动脉墙。动脉粥样硬化病变中的巨噬细胞占用并储存大量脂质它们被激活以产生炎症细胞因子和生长因子。自由的当地满意胆固醇会导致巨噬细胞内部和细胞外空间内形成晶体。炎症动脉粥样硬化病变中的免疫反应是临床发展的关键致病因素疾病。但是，导致动脉粥样硬化病变中感染激活的因素仍然存在未知。免疫细胞识别并应对对宿主有危险的疾病，例如感染，癌症，组织损伤或代谢发展。免疫细胞表达可以识别外国的接收器来自微生物的分子以及在病理条件下出现的改变的自分子。它有最近被证明，正常固体物质的结晶被认为是对宿主的危险，可以导致胞质受体复合物Nalp3炎症体的激活。我们发现胆固醇在动脉粥样硬化病变中绝对存在的晶体可以激活Nalp3炎症体免疫细胞导致caspase-1介导的成熟和促炎性细胞因子IL-1？和IL-18。我们的假设是胆固醇晶体充当内源性危险信号并激活NALP3 炎症。我们假设胆固醇晶体诱导的免疫激活对于动脉粥样硬化病变中炎症的发展，可能会影响主动性和发展动脉粥样硬化疾病。我们建议通过分析用小鼠用炎性途径的成分中的靶向病变。淘汰小鼠的巨噬细胞将是在体内将测试经过体外和胆固醇晶体诱导的炎症的分析。更好地了解如何晶体可以进入巨噬细胞并在发起信号的地方，我们将使用共聚焦成像将图像晶体与高空间分辨率的荧光结构一起使用的技术。我们将测试使用小鼠动脉粥样硬化模型的Nalp3炎性体激活的生物学相关性缺乏炎症体（NALP3和ASC）途径的LDL受体和成分的敲除小鼠。我们将进一步评估不同人类动脉硬化病变类型中晶体的患病率细胞和充气体激活标志物，以了解人类晶体的相关性动脉粥样硬化疾病。详细了解免疫细胞胆固醇晶体识别的分子机制将有助于针对动脉粥样硬化的发作和进展的新型热目标的鉴定，可能会产生广泛的临床和社会经济影响。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome.

DOI：
10.1002/eji.201040425
发表时间：
2010-06
期刊：
EUROPEAN JOURNAL OF IMMUNOLOGY
影响因子：
5.4
作者：
Kim, Sarah;Bauernfeind, Franz;Ablasser, Andrea;Hartmann, Gunther;Fitzgerald, Katherine A.;Latz, Eicke;Hornung, Veit
通讯作者：
Hornung, Veit

NLRC3 puts the brakes on STING.